NHGRI continues to push the boundaries of innovation
By Steven Benowitz
Associate Director of Communications, Extramural Research Program
At the meeting - held February 11-12 in Rockville, Md. - council members heard about The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Human Heredity and Health in Africa (H3Africa) project. There was also a discussion of the status of the Centers of Excellence in Genomic Science (CEGS), a centerpiece of NHGRI's Extramural Research Program.
The goal of TCGA, a flagship program that NHGRI co-funds with the National Cancer Institute (NCI), is to understand the molecular basis of cancer by carefully examining the genomes of individual cancers, looking specifically for alterations in DNA and RNA and how such changes drive the disease. Begun in 2006 as a three-year pilot program, its aim was to fully analyze more than 10,000 specimens of 20 tumor types by 2014. TCGA is well on its way to achieving that ambitious goal, having just passed the program's midpoint, with data from 25 tumor types available, including breast, ovarian, lung, colorectal and brain cancers. Some results have been unexpected, according to TCGA program director Brad Ozenberger, Ph.D., who is also deputy director of NHGRI's Division of Genomic Medicine.
"Our goal was to create a large community data set," he said, "but we didn't anticipate how quickly our data would translate into clinical utility."
In the case of glioblastoma (brain) tumors, for example, TCGA findings helped explain drug resistance patterns, immediately indicating treatment changes for some patients. In the case of ovarian cancers, findings showed both new potential drug targets and the need for customized therapies. The first genomic look at lung squamous cell carcinoma has also led to new diagnostic and therapeutic targets.
"In establishing a comprehensive atlas of mutations, TCGA has been successful in beginning to help us understand what is driving common cancers, both their initiation and progression," Dr. Ozenberger said. "We're starting to see TCGA data enter clinical practice, where there is an increasing emphasis on genomic analyses and in therapy customized for individual cancer patients."
TCGA will wind down in 2015. NCI and NHGRI will continue to work together and separately to develop new initiatives, including new clinical studies that will explore the genomic underpinnings of metastasis and individuals' response to therapy.
GTEx and H3Africa are two newer programs, both launched in 2010. They are supported by the National Institutes of Health (NIH) Common Fund, far-reaching, trans-institute initiatives designed to speed the movement of research discoveries from the bench to the bedside.
GTEx aims to establish a resource database and tissue bank to study how inherited genetic variants may influence gene activity and lead to common disease, explained GTEx program director Simona Volpi, Ph.D. Scientists are collecting more than 30 tissue types, which come from autopsy or organ and tissue transplant programs. Both DNA and RNA are analyzed from samples to catalog genetic variants and gene expression, respectively.
"GTEx is a very complex program and has a lot of moving parts," Dr. Volpi said, citing a sample and data repository, a centralized laboratory, and a data analysis and coordinating center. By the end of the two-year pilot, there will be seven organ sites associated with at least 100 donors each and two organ sites associated with at least 90 donors analyzed for gene expression. The program will eventually include tissue from 900 deceased donors, more than 25,000 healthy tissue samples collected and more than 20,000 data sets analyzed. Ultimately, GTEx will provide an "atlas of human gene expression."
Dr. Volpi noted that another study, which falls under the ethical, legal and social implications arm of the program, involves interviewing donor families to examine the process of consent for tissue donation.
H3Africa is a truly international program. A partnership between the U.K Wellcome Trust and the NIH, H3Africa supports the development of an African, continent-wide genomics research and training infrastructure. The program will help develop expertise and foster collaboration among African scientists, establish investigator networks for research collaborations, and contribute to training the next generation of investigators.
"We are funding centers and collaborative projects, which doesn't happen often in Africa," said H3Africa project coordinator Jane Peterson, Ph.D., senior advisor to the Office of the NHGRI Director, noting how the program has begun to establish that collaborative research culture in Africa. All grantees share specimens in a repository, and all applications must include a training component. In the first year of the program, the program funded two collaborative projects for metabolic syndrome and kidney disease, and two pilot biorepositories, in addition to establishing an African-wide bioinformatics network. Participation has been strong, with applications from 12 countries, representing collaborations among 20 countries and 98 institutions.
If H3Africa represents a commitment from NHGRI to the future genomic health of Africa, then NHGRI's CEGS program could be seen as a headfirst leap into the future of all of genomics. Begun in 2001, CEGS brings together multi-institution, interdisciplinary teams to develop new technologies and genomics concepts, new ways to analyze data and new approaches to solve genomics problems. In essence, it's NHGRI's engine of innovation.
"These are projects that by nature are risky," said Jeffery Schloss, Ph.D., director of the Division of Genome Sciences at NHGRI. "We want to use these funds to enable projects that can't be funded through any other grant mechanism. These are investigator-initiated topics, and very interdisciplinary and synergistic."
Projects are typically funded around $3 million per year for roughly five years. Applicants can reapply once for a maximum of 10 years of support, though not all are awarded at five years and not all at the maximum dollar amount. NHGRI funds a maximum of about 10 projects, which could total up to $30 million, though funding has never gone above $25 million. The commitment for Fiscal Year 2014 is currently at $14 million. The National Institute of Mental Health has also contributed more than $5.5 million over the life of the program.
The applications are complicated, and the process is highly selective. Of 75 applications, there have been 15 awards, and only five grants have been renewed out of 12 applications for renewal.
Following presentations by CEGS-supported researchers (and council members) David Kingsley, Ph.D., and Deirdre Meldrum, Ph.D., council members attending the meeting lauded the CEGS program. Robert Nussbaum, M.D., chief, division of medical genetics, University of California, San Francisco, called it "a fantastic program," particularly because it is investigator-initiated and promotes "risky science." He said that an under 50 percent success rate for renewal suggests the program is too small. Dr. Meldrum agreed. "I don't see any other program like this across NIH," she said.
In a separate presentation, Gary Gibbons, M.D., the newly appointed director of the National Heart, Lung, and Blood Institute (NHLBI), part of NIH, discussed priorities for NHLBI, including investigator-initiated science and a balanced research portfolio of basic, translational, clinical and population science. He stressed the need for a diverse biomedical workforce that reflects the diversity of the nation.
Dr. Gibbons discussed NHLBI's role in translating research results into improving public health, which he termed the "declining curve of cardiovascular mortality." He suggested that the challenge was to continue to "bend the curve even further to reduce those events," and called racial inequities a "special prism" through which to better understand how to achieve this. He described ecosystems of cardiovascular health inequities as a complex mix of biology/genetics and social/environmental influences, and as a root of differences in disease among various groups. Scientific evidence of this "bio-social" interplay ranges from studies tracking the influence of social networks in the development of obesity to genomic differences in the microbiome - the body's complement of microbes and their genomes - and its role in health disparities among racial and ethnic groups.
Dr. Gibbons cited a study showing that biological differences - in this case, a gene variant known to increase the risk of kidney disease in African Americans - can be turned into a genomics-based therapeutic strategy against the disease. Looking to the not-too-distant future and the potential benefits of genomics-based medicine, he asked, "What if we could identify a risk population, and develop a strategy that's actually preemptive in the development of this end-stage disease in a way that would be transformative to the patients?"
The next NHGRI council meeting will take place May 20-21, 2013 in Rockville.